Gastric or rectal instillation of short-chain fatty acids stimulates epithelial cell proliferation of small and large intestine in rats.
Short-chain fatty acids stimulate gut epithelial cell proliferation in vivo, although the difference between oral and rectal routes is unknown. Accordingly, we examined the effect of oral or rectal administration of these acids. We instilled a mixture of acetic acid, propionic acid, and n-butyric acid (150, 60, and 60 mmol/liter, respectively; pH 6.5) or saline (270 mM, pH 6.5) into the stomach (2 ml) or rectum (1 ml) three times daily for five days in rats fed an elemental diet. We measured crypt cell production rate of the jejunum, ileum, and distal colon of these rats. The crypt cell production rate of these segments was higher in rats with gastric or rectal instillation of short-chain fatty acids than in saline controls. The rectal route was slightly more effective than the gastric route. The above results indicated that the instillation of short-chain fatty acids orally or rectally stimulated gut epithelial cell proliferation.


Thoughts and Considerations of Women With Bipolar Disorder About Family Planning and Pregnancy: A Qualitative Study.
Women with bipolar disorder have an increased risk of relapse during pregnancy and the postpartum period, and they often express broad concerns about family planning. To explore the thoughts and considerations of women of childbearing age with bipolar disorder, about family planning and pregnancy. A qualitative study was conducted: 15 women with bipolar I disorder were individually interviewed. Content analysis was applied. Women worried about heritability of bipolar disorder, medication issues, and risk of relapse during pregnancy. They mentioned their fear to be incompetent as a mother during future mood episodes. Support of partner, family/friends, and professionals was mentioned as essential. Family planning is an essential topic in the treatment of every woman with bipolar disorder of childbearing age. These women expect early consultation with professionals for support, and specific information about heritability of the illness and use of medication during and after pregnancy.


The Fraser complex interconnects tissue layers to support basal epidermis and osteoblast integrated morphogenesis underlying fin skeletal patterning.
Fraser Syndrome is a rare, multisystemic autosomal recessive disorder characterized by disrupted epithelial-mesenchymal associations upon loss of Fraser Complex genes. Disease manifestation and affected organs are highly variable. Digit malformations such as syndactyly are common but of unclear developmental origins. We explored if zebrafish fraser extracellular matrix complex subunit 1 (fras1) mutants model Fraser Syndrome-associated appendicular skeleton patterning defects. Approximately 10% of fras1 mutants survive to adulthood, displaying striking and varied fin abnormalities, including endochondral bone fusions, ectopic cartilage, and disrupted caudal fin symmetry. The fins of surviving fras1 mutants frequently have fewer and unbranched bony rays. fras1 mutant fins regenerate to their original size but with exacerbated ray branching and fin symmetry defects. Single cell RNA-Seq analysis, in situ hybridizations, and antibody staining show specific Fraser complex expression in the basal epidermis during regenerative outgrowth. Fras1 and Fraser Complex component Frem2 accumulate along the basal side of distal-most basal epidermal cells. Greatly reduced and mislocalized Frem2 accompanies loss of Fras1 in fras1 mutants. The Sonic hedgehog signaling between distal basal epidermis and adjacent mesenchymal pre-osteoblasts that promotes ray branching persists upon Fraser Complex loss. However, fras1 mutant regenerating fins exhibit extensive sub-epidermal blistering associated with a disorganized basal epidermis and adjacent pre-osteoblasts. We propose Fraser Complex-supported tissue layer adhesion enables robust integrated tissue morphogenesis involving the basal epidermis and osteoblasts. Further, we establish zebrafish fin development and regeneration as an accessible model to explore mechanisms of Fraser Syndrome-associated digit defects and Fraser Complex function at epithelial-mesenchymal interfaces.


Measuring recovery after a hip fracture using the SF-36 and Cummings scales.
The objective of this study was to assess outcomes of traditional treatment of fractures using the SF-36 and the Cummings Hip Scale. In designing randomized clinical trials, it is necessary to determine the timing of assessment either for progress or for the main outcome. We set out to document the recovery of patients after surgery for hip fracture using current standard methods of medical care. This was a prospective study of a cohort of patients. Patients who were receiving standard medical care completed the SF-36 and the Cummings Hip Scale at previously determined times postoperatively. The SF-36 has eight subscales, including assessments of physical function, physical role behaviors, bodily pain, mental health, social role, emotional role, vitality and general health. Thirty-eight patients completed the questionnaires at 1 year postoperatively as well as previous time points. On the Cummings Hip Scale and the physical function, bodily pain, mental health, social function, emotional role, vitality and general health subscales of the SF-36, recovery is near complete at 6 months. Only the physical role subscale differs, with a statistically significant difference between the values at 6 months and 1 year, (p = 0.02). Patients attained over 90% of the 1 year value by 6 months for all except the physical role subscale. The physical role subscale reached 85%. For a hip fracture patient who is on the road to recovery, the majority of the recovery has therefore taken place by 6 months.


Relationship Between FDG Uptake and the Platelet/lymphocyte Ratio in Patients With Breast Invasive Ductal Cancer.
We investigated the relationship between F18-fluorodeoxyglucose (FDG) uptake and the platelet/lymphocyte ratio (PLR), as both represent inflammation. We retrospectively analyzed the cases of 143 consecutive invasive ductal carcinoma patients who had undergone preoperative FDG-PET and surgery. We divided the patients into groups based on their maximum standardized uptake value (SUVmax) values: low (<2.5) and high (≥2.5) and based on their PLRs: low (<130) and high (≥130). We determined the relationships between the SUVmax or PLR and clinicopathological features. Seventy-three patients (51.0%) had a high SUVmax in their primary tumor. There were significant associations between SUVmax and the PLR. A multivariate analysis revealed that high PLR, but not NLR, was independent factor associated with a high SUVmax. Seventy-four patients (51.7%) had a high PLR; The factors significantly associated with high PLR were large tumor size, presence of node metastasis, presence of vascular invasion, high NLR, and high SUVmax. In breast cancer patients, the PLR is independently associated with the SUVmax, but not with recurrent disease. In breast cancer patients with a high SUVmax and/or PLR, these values may reflect the tumor microenvironment.


Improved cloning vectors and transformation procedure for Lactococcus lactis.
Four shuttle vectors (pMIG 1, 2, 2H and 3) have been constructed based on the broad host-range plasmid pCK1. All the pMIG vectors possess a multiple cloning site containing 12 or more unique restriction enzyme sites, and are stably maintained at either high or low copy number in Lactococcus lactis and in Escherichia coli. By cloning the E. coli pUC replicon into one of these vectors a plasmid was constructed which can replicate to high copy number in recA strains of E. coli. The broad host-range of the pCK1 replicon may enable these cloning vectors to be used in a number of Gram-positive bacteria. One of these vectors was used to optimize an electroporation procedure for transformation of a commonly used plasmid-cured strain MG1363 of L. lactis which routinely yielded 1 x 10(7) to 5 x 10(7) transformants micrograms-1 supercoiled DNA using stored, snap-frozen cells. This transformation efficiency was obtained by growing the cells in medium containing the cell wall weakening agent glycine, to an upper limit of 2.5% w/v. Although growth of L. lactis strain MG1363 was inhibited by the use of 0.5 mol l-1 sucrose as an osmotic stabilizer, the presence of sucrose in the electroporation buffer was critical for high transformation efficiency. Other variables which were tested for their effect on the efficiency of transformation were cell concentration, DNA concentration, pulse time and field strength. These results provide a model procedure which can be followed to optimize conditions for the genetic transformation of various strains of L. lactis.


Bis(1-acetonylpyridinium) pyridinium hexaiodobismuth(III).
The crystal structure of the title complex, (C(8)H(10)N)(2)(C(5)H(6)N)[BiI(6)], contains discrete [BiI(6)](3-) anions, and (HNC(5)H(5))(+) and (CH(3)COCH(2)NC(5)H(5))(+) cations separated by normal van der Waals contacts. The [BiI(6)](3-) anion has the Bi atom on an inversion centre. The (HNC(5)H(5))(+) cation also lies about an inversion centre and is disordered. The (CH(3)COCH(2)NC(5)H(5))(+) cation lies in a general position.


A Novel Loss-of-Function MKRN3 Variant in a Chinese Patient With Familial Precocious Puberty: A Case Report and Functional Study.
Background: Central precocious puberty (CPP) is one of the most common and complex problems in clinical pediatric endocrinology practice. Mutation of the MKRN3 gene can cause familial CPP. Methods and Results: Here we reported a Chinese patient bearing a novel MKRN3 mutation (c.G277A/p.Gly93Ser) and showing the CPP phenotype. Functional studies found that this mutation of MKRN3 attenuated its autoubiquitination, degradation, and inhibition on the transcriptional activity of GNRH1, KISS1, and TAC3 promoters. Conclusion: MKRN3 (Gly93Ser) is a loss-of-function mutation, which attenuates the inhibition on GnRH1-related signaling, suggesting that this mutant can lead to central precocious puberty.


Recovery of peripheral lymph cells from congenitally athymic nude rats.
Thoracic-duct cannulation of mesenteric lymphadenectomized (MLNx) congenitally athymic nude rats was studied as a method of obtaining peripheral lymph cells. A higher recovery of non-lymphoid cells (NLC) was obtained from nude than from euthmyic littermates. Both a higher percentage and a greater number of NLC were found in nude animals. Most of these cells resembled dendritic or veiled cells and were strongly positive for Ia antigens. This population could further be enriched by irradiation of the animal, but with a risk of cell damage. Splenectomy had no effect on early output of Ia+ NLC. A substantial population of lymphoid cells from MLNx nude rats expressed T-cell antigens defined by the monoclonal antibodies OX 19, OX 8 or W3/25. These cells were more radiosensitive than were mature T cells. In addition, a large population of cells in the peripheral lymph from nude rats did not display surface antigens recognized by monoclonal antibodies directed either against B cells or against T cells. This cell fraction increased after irradiation. These cells resembled small lymphocytes but had a more irregular nucleus and multiple large granules.


Inference for multi-state models from interval-censored data.
Clinical statuses of subjects are often observed at a finite number of visits. This leads to interval-censored observations of times of transition from one state to another. The likelihood can still easily be written in terms of both transition probabilities and transition intensities. In homogeneous Markov models, transition probabilities can be expressed simply in terms of transition intensities, but this is not the case in more general multi-state models. In addition, inference in homogeneous Markov models is easy because these are parametric models. Non-parametric approaches to non-homogeneous Markov models may follow two paths: one is the completely non-parametric approach and can be seen as a generalisation of the Turnbull approach; the other implies a restriction to smooth intensities models. In particular, the penalized likelihood method has been applied to this problem. This paper gives a review of these topics.


Pathophysiology of glial growth factor receptors.
Activation and proliferation of glial cells are common events in the pathology of the nervous system. Although we are only beginning to understand the molecular signals leading to glial activation in vivo, there is increasing evidence that growth factors and their receptors may play an important part. In this paper we summarize the data on the pathophysiology of glial growth factor receptors and their ligands in the central and peripheral nervous systems.


Highly enriched CD133(+)CD44(+) stem-like cells with CD133(+)CD44(high) metastatic subset in HCT116 colon cancer cells.
Stem-like cancer cells (SLCCs) are distinct cellular subpopulation in colon cancer that is essential for tumor maintenance. Previous studies indicated that SLCCs accounted for only a minor subset in a given cancer model. However, we found that SLCCs frequency varied among a panel of colon cancer cell lines, with HCT116 cells composed mainly of SLCCs, as demonstrated by colonosphere forming capability and CD133 expression. Indeed, flow cytometric analysis revealed more than 60% HCT116 cells co-expressed the putative SLCCs markers CD133 and CD44. Compared with non-CD133(+)CD44(+) cells, FACS sorted CD133(+)CD44(+) cells were undifferentiated, endowed with extensive self-renewal and epithelial lineage differentiation capacity in vitro. CD133(+)CD44(+) exhibited enhanced tumorigeneicity in NOD/SCID mice. One thousand CD133(+)CD44(+) cells initiated xenograft tumors efficiently (3/6) while 1 × 10(5) non-CD133(+)CD44(+) cells could only form palpable nodule with much slower growth rate (1/6). More interestingly, long-term cultured self-renewing CD133(+)CD44(+) cells enriched CD133(+)CD44(high) subset, which expressed epithelial to mesenchymal transition marker, were more invasive in vitro and responsible solely for liver metastasis in vivo. In conclusion, these data demonstrated for the first time that CD133(+)CD44(+) SLCCs were highly enriched in HCT116 cells and that metastatic SLCCs resided exclusively in a CD133(+)CD44(high) subpopulation.


Bacillus Calmette-Guérin revaccination questionable with low tuberculosis incidence.
Bacillus Calmette-Guerin (BCG) revaccination was discontinued in Finland in 1990. The objective of this study was to assess the impact of BCG revaccination of tuberculin-negative school-children in prevention of tuberculosis. The tuberculosis cases in 1990-1995 were calculated among age cohorts born 1979-1984 and no longer covered by the BCG revaccination program. Corresponding data were collected for comparison from the period of revaccination in 1980-1985 among age cohorts born in 1969-1974. The National Tuberculosis Register was reviewed in order to observe the tuberculosis trend since 1980 in the age groups of 10-14 and 15-19 yr. Three cases of tuberculosis have been registered among non-BCG-revaccinated children during 6 yr after discontinuation of the program, i.e., 2.23 cases (95% CI 0.72 to 6.90) per million person yr. The control group revealed five cases, 3.78 (95% CI 1.57 to 9.07) per million person yr. The relative risk of tuberculosis in non-BCG-revaccinated children is 0.59 (95% CI 0.14 to 2.47) compared with the control group. The incidence of tuberculosis has continued to decline among adolescents since 1980. The follow-up data confirm that the cessation of BCG revaccination program had no effect on the continuing overall decline of tuberculosis in Finland. The efficacy of BCG revaccination seems to be low or nonexistent in countries with low tuberculosis incidence.


High-resolution structural and thermodynamic analysis of extreme stabilization of human procarboxypeptidase by computational protein design.
Recent efforts to design de novo or redesign the sequence and structure of proteins using computational techniques have met with significant success. Most, if not all, of these computational methodologies attempt to model atomic-level interactions, and hence high-resolution structural characterization of the designed proteins is critical for evaluating the atomic-level accuracy of the underlying design force-fields. We previously used our computational protein design protocol RosettaDesign to completely redesign the sequence of the activation domain of human procarboxypeptidase A2. With 68% of the wild-type sequence changed, the designed protein, AYEdesign, is over 10 kcal/mol more stable than the wild-type protein. Here, we describe the high-resolution crystal structure and solution NMR structure of AYEdesign, which show that the experimentally determined backbone and side-chains conformations are effectively superimposable with the computational model at atomic resolution. To isolate the origins of the remarkable stabilization, we have designed and characterized a new series of procarboxypeptidase mutants that gain significant thermodynamic stability with a minimal number of mutations; one mutant gains more than 5 kcal/mol of stability over the wild-type protein with only four amino acid changes. We explore the relationship between force-field smoothing and conformational sampling by comparing the experimentally determined free energies of the overall design and these focused subsets of mutations to those predicted using modified force-fields, and both fixed and flexible backbone sampling protocols.


Intravascular papillary endothelial hyperplasia of the central nervous system--four case reports.
Four rare cases of intracranial intravascular papillary endothelial hyperplasia (IPEH) manifesting as cranial nerve disturbances occurred in 16-, 18-, 24-, and 28-year-old females. Magnetic resonance imaging showed all lesions as isointense with strong enhancement on T1-weighted images, and as hyperintense on T2-weighted images. All lesions were removed via craniotomies. Histological examination found vascular structures and papillary spaces lined with endothelial cells showing immunoreactivity for CD31. Complete removal was curative in two cases, whereas incomplete removal resulted in cure in one case and residual deficits in one case. Iatrogenic deficits should be avoided in IPEH treatment by surgery. Differentiation from neoplasm such as angiosarcoma depends on histological characteristics.


Toward a general theory of stereopsis: binocular matching, occluding contours, and fusion.
Models of stereopsis have focused on developing strategies for identifying common features in the 2 half-images so that disparity may be computed. This emphasis ignores the unpairable features that arise at occluding contours (half-occlusions). Most models treat half-occlusions as noise or outliers that are interpreted after disparity processing is completed. A series of experiments reveal that occlusion relationships are sensed during the earliest stages of binocular processing. The authors hypothesize the existence of receptive field structures that sense the local structure of stereoscopic occlusion relationships to account for these findings. Finally, a simple theoretical framework is presented in which fusion, stereopsis, and occlusion are unified. This theory explains the co-occurrence of stereopsis and diplopia and how half-occlusions escape the suppression characteristic of binocular rivalry.


Treatment of alcoholism in Germany.
Alcohol dependence is associated with a wide range of physical, mental, and social harms. The related economic and social costs can be reduced by an adequate addiction therapy. This therapy should not only focus on the psychotherapy of addiction but should also include the possibility to treat psychiatric co-morbidity and take into account gender-specific aspects of addiction. The first steps of reintroducing the patient to employment are also of major importance especially in areas of high jobless rates. A highly efficient system of addiction treatment has evolved in Germany over the past decades. Ambulant treatment centers, units offering "qualified alcohol withdrawal programs", and inpatient addiction therapy programs are closely interlinked with each other. The Friedrich-Petersen-Klinik in Rostock is presented as an example. The therapeutic needs of the patients and the social situation of north-eastern Germany are reflected in the concept of the Clinic. It is shown how the Friedrich-Petersen-Klinik integrates with other therapeutic modalities to ensure a continuous attendance over many months on the patient's way to stable abstinence.


Antioxidant status and purine bases in carotid artery plaque.
Free radical excess and oxidative stress are implicated in the formation and progression of atherosclerotic plaque through actions on susceptible vascular cells, such as by activating xanthine oxidase. Purine bases and other antioxidant compounds could play important protective roles in atherogenesis, as could nonenzymatic low molecular weight thiol defenses, not previously evaluated in carotid artery plaque. Therefore, we measured purine catabolites (hypoxanthine, xanthine, uric acid, allantoin) and antioxidant compounds (total sulphydryl groups, homocysteine, cysteine, and glutathione) in advanced carotid artery plaque and found a high ratio of allantoin to uric acid, suggesting a ongoing local oxidative stress.


Differences in cephalometric reference values between five centres: relevance to the Eurocleft Study.
Cephalometric data from five different geographical areas (Oslo, Manchester, London, Nijmegen, and Michigan) were compared. The angles SNA, SNB, and ANB were taken from published tables in the form of mean, standard deviation (SD) and number in the sample, divided up by age and sex. Angles SNA and SNB were significantly different among centres on univariate analysis. The Oslo data showed 23 instances in which they differed significantly from the other data, London 16, Manchester 11, Nijmegen 11, and Michigan 7. Multivariate analysis using Penrose distances were Oslo (2.04), Manchester (1.39), London (0.93), Nijmegen (0.80), and Michigan (0.66). The sums of the Mahalanobis distances were Nijmegen (3.60), Oslo (3.10), London (2.80), Manchester (2.25), and Michigan (1.49). As these results probably reflect racial and genetic differences, these must be taken into account when international comparisons are being made, as in the Eurocleft study.


Crystallization and preliminary crystallographic study of a trypsin-resistant catalytic domain of human calcineurin.
Calcineurin, a Ca(2+)/calmodulin-dependent serine/threonine protein phosphatase, plays a key role in a number of cellular pathways, including T-cell activation, and is an important molecular target of the immunosuppressive drugs cyclosporin A and FK506. To understand the structural basis underlying the activation of calcineurin by calmodulin, X-ray crystallography was employed to solve the three-dimensional structure of the free calcineurin catalytic domain (residues 20-347 of the A subunit). To accomplish this, a bacterially expressed glutathione S-transferase (GST) fusion protein of the human calcineurin catalytic domain was first purified by GST-affinity chromatography. After limited digestion by trypsin, the catalytic domain (Cncat) was purified using anion-exchange and size-exclusion chromatography. Crystallization of Cncat was achieved by the hanging-drop vapour-diffusion method at pH 6.5 using PEG 6000 as precipitant. The diffraction results showed that the Cncat crystal belonged to the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 161.6, b = 87.4, c = 112.0 Å. There are four Cncat molecules in the asymmetric unit, with 49.5% solvent content. An X-ray diffraction data set was collected to 2.87 Å resolution and a clear molecular-replacement solution was obtained. The active site of Cncat is open to the solvent channels in the crystal packing.


Insight into Discovery of Next Generation Reversible TMLR Inhibitors Targeting EGFR Activating and Drug Resistant T790M Mutants.
Epidermal growth factor receptor (EGFR) is a well-recognised drug target exploited for treating non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are first generation clinically employed inhibitors used against EGFR activating mutants. However, during course of treatment these inhibitors become ineffective due to the emergence of an acquired secondary mutation. Subsequently, in order to overcome non-responsiveness second and third generation inhibitors were designed having covalent bond and irreversible mode of action. However, these inhibitors were shown to be toxic. This led to the discovery of lead candidates with completely different mode of action and therapeutic efficacy. We have reviewed the recent efforts undertaken by researchers in discovering newer noncovalent reversible next generation inhibitors for treating NSCLC. We first studied the optimization steps and pharmacokinetic variables of the synthesised molecules. We also analysed bonds and interactions using PDB X-ray crystal structures as well as scaffold and selectivity analysis was undertaken. We identified that ligand lipophilic efficiency driven potency is a preferable optimisation parameter for maintaining drug likeliness of the molecule. Also, few h-bonds were recognised as major players in affecting the binding of compound. The scaffold analysis revealed that ligand molecules with pyrimidine core exhibit higher inhibitory activity against TMLR, as well as higher selectivity with respect to other kinases. Next generation reversible inhibitors exhibited unique binding mode and were found to occupy three major pockets (ribose pocket, back pocket and hinge region), which is critical for increasing the selectivity of the compound against TMLR mutants.


Domains of quality for clinical ethics case consultation: a mixed-method systematic review.
"Clinical ethics consultation" (CEC) is the provision of consultative services by an individual or team with the aim of helping health professionals, patients, and their families grapple with difficult ethical issues arising during health care. There are almost 25,000 articles in the worldwide literature on CEC, but very few explicitly address measuring the quality of CEC. Many more address quality implicitly, however. This article describes a rigorous protocol for compiling the diverse literature on CEC, analyzing it with a quality measurement lens, and seeking a set of potential quality domains for CEC based on areas of existing, but hitherto unrecognized, consensus in the literature. This mixed-method systematic review will follow a sequential pattern: scoping review, qualitative synthesis, and then a quantitative synthesis. The scoping review will include categorizing all quality measures for CEC discussed in the literature, both quantitative and qualitative. The qualitative synthesis will generate a comprehensive analytic framework for understanding the quality of CEC and is expected to inform the quantitative synthesis, which will be a meta-analysis of studies reporting the effects of CEC on pre-specified clinical outcomes. The literature on CEC is broad and diverse and has never been examined with specific regard to quality measurement. We propose a novel mixed-methods approach to compile and synthesize this literature and to derive a framework for assessing quality in CEC. PROSPERO CRD42015023282.


Quality standards for child and adolescent mental health in primary care.
Child and adolescent mental health problems are common in primary healthcare settings. However, few parents of children with mental health problems express concerns about these problems during consultations. Based on parental views, we aimed to create quality of care measures for child and adolescent mental health in primary care and develop consensus about the importance of these quality standards within primary care. Quality Standards were developed using an iterative approach involving four phases: 1) 34 parents with concerns about their child's emotional health or behaviour were recruited from a range of community settings including primary care practices to participate in focus group discussions, followed by validation groups or interviews. 2) Preliminary Quality Standards were generated that fully represented the parents' experiences and were refined following feedback from an expert parent nominal group. 3) 55 experts, including parents and representatives from voluntary organisations, across five panels participated in a modified two-stage Delphi study to develop consensus on the importance of the Quality Standards. The panels comprised general practitioners, other community-based professionals, child and adolescent psychiatrists, other child and adolescent mental health professionals and public health and policy specialists. 4) The final set of Quality Standards was piloted with 52 parents in primary care. In the Delphi process, all five panels agreed that 10 of 31 Quality Standards were important. Although four panels rated 25-27 statements as important, the general practitioner panel rated 12 as important. The final 10 Quality Standards reflected healthcare domains involving access, confidentiality for young people, practitioner knowledge, communication, continuity of care, and referral to other services. Parents in primary care agreed that all 10 statements were important. It is feasible to develop a set of Quality Standards to assess mental healthcare provision for children and adolescents seen within primary healthcare services. Primary care practitioners should be aware of parental perspectives about quality of care as these may influence help-seeking behaviours.


Epithelial sodium channel abundance is decreased by an unfolded protein response induced by hyperosmolality.
Large shifts of osmolality occur in the kidney medulla as part of the urine concentrating mechanism. Hyperosmotic stress profoundly challenges cellular homeostasis and induces endoplasmic reticulum (ER) stress. Here, we examined the unfolded protein response (UPR) in hyperosmotically-challenged principal cells of the kidney collecting duct (CD) and show its relevance in controlling epithelial sodium channel (ENaC) abundance, responsible for the final adjustment of Na(+) excretion. Dehydration increases medullary but not cortical osmolality. Q-PCR analysis of microdissected CD of water-deprived mice revealed increased aquaporin-2 (AQP2) expression in outer medullary and cortical CD while ENaC abundance decreased in outer medullary but not cortical CD. Immunoblotting, Q-PCR and immunofluorescence revealed that hyperosmolality induced a transient ER stress-like response both ex vivo and in cultured CD principal cells and increased activity of the canonical UPR mediators PERK and ATF6. Both hyperosmolality and chemical induction of ER stress decreased ENaC expression in vitro. ENaC depletion by either stimulus was abolished by transcriptional inhibition and by the chemical chaperone 4-phenylbutyric acid and was partly abrogated by either PERK or ATF6 silencing. Our data suggest that induction of the UPR by hyperosmolality may help preserve body fluid homeostasis under conditions of dehydration by uncoupling AQP2 and ENaC abundance in outer medullary CD.


Ultrasonic measurement of aortic and umbilical blood flow in the human fetus.
The study reports blood velocity and blood flow in the descending aorta and the umbilical vein of 20 normal human fetuses by application of combined B-mode ultrasound and pulsed Doppler technique. All pregnancies and newborns were clinically normal. The echographic examination was performed between 37 and 40 weeks' gestation by an ADR real-time linear scanner 2130 coupled with the Kranzb uhler pulsed Doppler system 8105. The diameter of the vessels was measured by B-mode echogram, and the Doppler beam was directed to form an incident angle between 30 and 65 degrees with the axis of the vessel. The Doppler shift frequency was measured electronically with a spectrum analyzer 8106. Fetal blood velocity waveforms were calculated following the Doppler equation. In the descending aorta, the calculated velocity was 27.7 +/- 6.7 cm/second (mean +/- SD) and the blood flow was 679 +/- 106 ml/minute or 216 ml/kg/minute. In the umbilical vein, the same parameters were 18.3 +/- 4.0 cm/second, 366 +/- 65 ml/minute, and 117 +/- 16 ml/kg/minute, respectively. The average umbilical flow: aortic flow ratio was 0.54 +/- 0.07.


Prevalence, Age Distribution, and Risk Factors of Visual Inspection With Acetic Acid-Positive From 2007 to 2011 in Jakarta.
Cervical cancer is still the second most frequent cancer among Indonesian women, thus screening program is still critically important to prevent it. Visual inspection with acetic acid (VIA) was introduced as a method which is most suitable with Indonesia's condition compared with the other screening methods. The Female Cancer Program from Jakarta Regional collaborated with Leiden University in 2007 to 2011 has done cervical cancer screening using VIA method, involving 25,406 women spreading across several primary health centers in Jakarta. By using these data, we found out the prevalence, age distribution, and risk factor of VIA positive in Jakarta as a basis to predict the budget and logistics for the next cervical cancer screening and to do an advocating to the Jakarta's government. A secondary data analysis was conducted from several areas in Jakarta from 2007 to 2011. VIA test was used as the screening method, and performed by doctors and midwives with technical supervision by gynecologists. From 25,406 women, there were 1,192 cases (4.7%) of VIA test positive. The risk factors that can significantly influence the result of VIA positive were number of marriage, parity, smoking habits, and the use of hormonal contraception with OR 1.51, 1.85, 1.95, and 0.68, respectively. Prevalence of VIA test-positive is 4.7% in Jakarta population. The findings of precancerous lesions and cervical cancers are not only between thirty and fifty years old, but also below the thirty years old and after fifty years old. We suggest that VIA test should be performed to all reproductive age and elder women who are not screened yet.


Hypothermia Promotes Interleukin-22 Expression and Fine-Tunes Its Biological Activity.
Disturbed homeostasis as a result of tissue stress can provoke leukocyte responses enabling recovery. Since mild hypothermia displays specific clinically relevant tissue-protective properties and interleukin (IL)-22 promotes healing at host/environment interfaces, effects of lowered ambient temperature on IL-22 were studied. We demonstrate that a 5-h exposure of endotoxemic mice to 4°C reduces body temperature by 5.0° and enhances splenic and colonic il22 gene expression. In contrast, tumor necrosis factor-α and IL-17A were not increased. In vivo data on IL-22 were corroborated using murine splenocytes and human peripheral blood mononuclear cells (PBMC) cultured upon 33°C and polyclonal T cell activation. Upregulation by mild hypothermia of largely T-cell-derived IL-22 in PBMC required monocytes and associated with enhanced nuclear T-cell nuclear factor of activated T cells (NFAT)-c2. Notably, NFAT antagonism by cyclosporin A or FK506 impaired IL-22 upregulation at normothermia and entirely prevented its enhanced expression upon hypothermic culture conditions. Data suggest that intact NFAT signaling is required for efficient IL-22 induction upon normothermic and hypothermic conditions. Hypothermia furthermore boosted early signal transducer and activator of transcription 3 activation by IL-22 and shaped downstream gene expression in epithelial-like cells. Altogether, data indicate that hypothermia supports and fine-tunes IL-22 production/action, which may contribute to regulatory properties of low ambient temperature.


Comparison of B-Mode with B-Flow Sonography for the Evaluation of Femoral Arteries in Infants.
Purpose To evaluate femoral arteries (FAs) in infants in the context of catheter angiography with B-mode (BMS) and B-flow sonography (BFS) and to compare both methods for vessel delineation and reliability of vessel diameter measurements. Methods 21 consecutive infants who underwent ultrasound for the evaluation of FAs before or after cardiac catheterization were retrospectively included in this study. The diameter of the FAs and the maximum length of the vessel section displayed on a single ultrasound plane were recorded by two radiologists for BMS and BFS. The visual image quality was rated by one observer. Statistics included intraclass correlation coefficient, Bland-Altman analysis, Fisher´s exact test and t-test. Results The intraobserver as well as interobserver correlation was excellent for BMS (0.7922 and 0.6521) and BFS (0.8094 and 0.7637). The Bland-Altman analysis revealed limits of agreement for BMS between +/-0.73 mm (intraobserver) and +/-0.55 mm (interobserver) and for BFS between +/-0.83 mm (intraobserver) and +/-0.7 mm (interobserver). BFS allowed visualization of a longer stretch of the FA than BMS (length 3.54 +/-0.85 vs. 2.21 +/-0.9 cm, p < 0.0001). The image quality was significantly higher for BFS (p = 0.0043). Conclusion Since BFS shows excellent reproducibility for vessel measurements and superior image quality in infants, if available, BFS should be included in standard protocols when realistic measurements are required. Key Points · B-flow sonography offers high image quality for the evaluation of femoral arteries.. · Femoral artery diameter measurements performed with B-flow sonography show excellent reproducibility.. · If available, additional B-flow sonography of femoral arteries in infants is recommended.. Citation Format · Groth M, Dammann E, Arndt F et al. Comparison of B-Mode with B-Flow Sonography for the Evaluation of Femoral Arteries in Infants. Fortschr Röntgenstr 2017; 189: 1161 - 1167.


Phosphorus and Cu2+ removal by periphytic biofilm stimulated by upconversion phosphors doped with Pr3+-Li.
Upconversion phosphors (UCPs) can convert visible light into luminescence, such as UV, which can regulate the growth of microbes. Based on these fundamentals, the community composition of periphytic biofilms stimulated by UCPs doped with Pr3+-Li+ was proposed to augment the removal of phosphorus (P) and copper (Cu). Results showed that the biofilms with community composition optimized by UCPs doped with Pr3+-Li+ had high P and Cu2+ removal rates. This was partly due to overall bacterial and algal abundance and biomass increases. The synergistic actions of algal, bacterial biomass and carbon metabolic capacity in the Pr-Li stimulated biofilms facilitated the removal of P and Cu2+. The results show that the stimulation of periphytic biofilms by lanthanide-doped UCPs is a promising approach for augmenting P and Cu2+ removal.


Cost-Effectiveness of Defibrotide in the Prophylaxis of Veno-Occlusive Disease after Pediatric Allogeneic Stem Cell Transplantation.
Veno-occlusive disease (VOD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic use of defibrotide (DF) might further reduce VOD rates but has no impact on the incidence of severe VOD or VOD-associated mortality. We investigated the cost-effectiveness of prophylactic DF according to the British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines in 348 children who underwent transplantation between 2001 and 2014 in our hospital, 138 of whom were at risk for VOD. The VOD incidence was 7.4% for the total cohort. Patients at risk had a higher incidence of VOD compared with patients without risk factors (15.2% versus 2.4%, P < .0001). VOD occurred more often in patients after busulfan-based myeloablative conditioning than in patients after total body irradiation (11.2% versus 3.5%, P = .001). Donor types or the transplantation-related mortality (TRM) risk score did not correlate with VOD incidence. In 81% of patients who responded to therapeutic DF, VOD resolved completely. Overall VOD-associated mortality was .3% for the complete cohort, 3.7% for patients diagnosed with VOD, and 20% for patients with severe VOD. Neither the cumulative incidence of TRM (19% ± 8% versus 17% ± 2%, P = .706) nor the median length of hospitalization differed between patients with VOD and patients without. The median costs per HSCT in patients with VOD were about one-third higher than the overall median costs per transplantation at our institution. The calculated total costs of prophylactic DF treatment for 138 patients at risk was almost 6 times as high as the incremental costs for patients with VOD. We conclude that prophylactic DF for children at risk for VOD is not cost-effective with respect to TRM and length of hospital stay.


'Mate' Intake, Hormone-Based Risk Factors and Breast Cancer: a Case-Control Study
Previous reports on the inverse association between 'mate' intake (infusion of Ilex Paraguariensis herb) and breast cancer (BC) risk led us to consider two main roles for the infusion: as a substantial antioxidant contributor and as a hormone regulator, particularly through anti-aromatase capacities. Since menstrual-reproductive risk factors for BC reflect women's estrogenic exposure during the reproductive lifespan, and considering that 'mate' intake exerts putative stronger protection among high antioxidant contributors, we attempted to analyze interactions among the infusion, hormon-linked reproductive factors and BC risk, which have hitherto remained unexplored. We analyzed a database of 572 BC incident cases and 889 controls. Women were interviewed with a specific questionnaire featuring socio-demographic, lifestyle and reproductive variables (age at menarche, 1st live birth and menopause; number of live births; breastfeeding months), and a food frequency questionnaire, focusing on 'mate' intake (consumer status, daily intake, age at start, age at quit, duration of habit). Odds ratios (OR) and their 95% confidence Intervals were calculated through unconditional logistic regression, adjusting for relevant potential confounders. 'Mate' intake showed strong inverse associations with some high-risk hormone-related factors: early menarche, nulliparity, low breastfeeding, long reproductive years and high number of ovulatory cycles. Moreover, all subsets of high dietary energy demonstrated even stronger associations. In conclusion, regarding exposure to known hormone risk factors, we found strong inverse associations between high 'mate' intake and BC, which were greater among those consuming higher calorific diets. Our analyses support possible combined antioxidant and antiestrogenic effects for 'mate' infusions.


The value of positron emission tomography/computed tomography for evaluating metastatic disease in patients with pancreatic cancer.
Routine application of positron emission tomography/computed tomography (PET/CT) for pancreatic cancer staging remains a controversial approach. The purpose of this study was to reassess the clinical impact of PET/CT for the detection of distant metastasis of pancreatic cancer. From January 2006 to June 2009, 125 patients with histologically proven pancreatic cancer that had undergone PET/CT at our hospital were retrospectively reviewed. To evaluate the clinical efficacy of PET/CT on the management plan, the post-PET/CT management plans were compared with the pre-PET/CT management plans. After the conventional staging workup, we determined that 76 patients (60.8%) had resectable lesions, whereas 48 patients had unresectable lesions. One patient underwent explorative laparotomy due to equivocal resectability. Positron emission tomography/computed tomography diagnosed distant metastasis in only 2 (2.6%) of the 76 patients with resectable lesions, and these patients did not undergo unnecessary surgical treatment. Complete resection was not performed in 8 of the 74 operative patients because they had distant metastasis detected during the operative procedure. Positron emission tomography/computed tomography diagnosed distant metastasis in 32 of the 44 patients with metastatic lesions that were histologically shown to have sensitivity of 72.7%. Positron emission tomography/computed tomography has a limited role in the evaluation of metastatic disease from pancreatic cancer.


Risk factors in adolescents as predictors of arterial hypertension in adults: Protocol for a systematic review.
This is a protocol of a review paper, and there is no abstract. This review is part of a doctoral project that aims to develop a discrete event simulation model to predict how many adolescents may become hypertensive in adulthood. We will use data from the Brazilian study of cardiovascular risks in adolescents, called ERICA (Portuguese acronym). This study may help promote adherence to disease prevention protocols.


Singlet Oxygen in Plants: Generation, Detection, and Signaling Roles.
Singlet oxygen (1O2) refers to the lowest excited electronic state of molecular oxygen. It easily oxidizes biological molecules and, therefore, is cytotoxic. In plant cells, 1O2 is formed mostly in the light in thylakoid membranes by reaction centers of photosystem II. In high concentrations, 1O2 destroys membranes, proteins and DNA, inhibits protein synthesis in chloroplasts leading to photoinhibition of photosynthesis, and can result in cell death. However, 1O2 also acts as a signal relaying information from chloroplasts to the nucleus, regulating expression of nuclear genes. In spite of its extremely short lifetime, 1O2 can diffuse from the chloroplasts into the cytoplasm and the apoplast. As shown by recent studies, 1O2-activated signaling pathways depend not only on the levels but also on the sites of 1O2 production in chloroplasts, and can activate two types of responses, either acclimation to high light or programmed cell death. 1O2 can be produced in high amounts also in root cells during drought stress. This review summarizes recent advances in research on mechanisms and sites of 1O2 generation in plants, on 1O2-activated pathways of retrograde- and cellular signaling, and on the methods to study 1O2 production in plants.


In the zone: understanding zona reticularis function and its transformation by adrenarche.
The human adrenal cortex comprises three distinct zones with unique steroid products, namely the zona glomerulosa, which secretes the mineralocorticoids, the zona fasciculate, which secretes the glucocorticoids and the zona reticularis (ZR), which at adrenarche, begins to produce the so-called adrenal androgens. Of all the adrenal zones, we still understand control of ZR emergence the least, and yet the consequences of such dysregulation can be devastating. Premature adrenarche is a growing problem and the correspondingly inappropriate emergence of ZR function can negatively influence puberty and lead to adult infertility. Our understanding is limited and more needs to be done. The purpose of these three reviews is to provide a survey of where we are in our current understanding of what adrenarche is, and indeed if it is unique to humans at all. Furthermore, these reviews describe what is also known of how the functional ZR emerges during adrenarche and what steroids of physiologic relevance result beyond the widely known DHEA and DHEAS elevated at this time. Such advances in human, primate and indeed stem-cell biology are clearly laying the foundation for new directions in the hunt for the factors involved in the regulation and functional emergence of a ZR at the appropriate time, as well as insight into how they may fail. Given support for these new directions, considerable progress can clearly be made.


Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations.
Our objective was to compare the clinical and pathological characteristics of frontotemporal dementia patients with MAPT, GRN and C9orf72 gene mutations. We carried out a cross-sectional comparative study of 74 gene-positive patients (15 MAPT, 17 GRN and 42 C9orf72). Thirty had post mortem pathological data permitting clinico-pathological correlation. MAPT patients were younger than other groups, and showed more frequent behavioural disinhibition, repetitive and stereotyped behaviours, semantic impairment and temporal predominance of atrophy. GRN patients were older at death and more likely to present with non-fluent aphasia. C9orf72 patients alone showed a co-occurrence of ALS. They showed more psychotic symptoms and irrational behaviour, yet were more often reported clinically as socially appropriate and warm. They showed less dietary change than other groups. C9orf72 patients with and without ALS differed only in frequency of psychosis. Greater clinical overlap was observed between GRN and C9orf72 compared to MAPT cases. MAPT cases had tau and GRN and C9orf72, with one exception, TDP-43 pathology. Non-fluent aphasia was linked to TDP subtype A in both GRN and C9orf72 cases and ALS with subtype B. In conclusion, the findings reinforce clinical heterogeneity in FTD and strengthen evidence that genotype influences clinical presentation. Clinical features may inform targeted genetic testing.


Effect of lindane on antibody response to typhoid vaccine in weanling rats.
The immunosuppressive effect of lindane was assessed in weanling rats over a period of 5 weeks. Agglutinin titres against S. typhi 'O' and 'H', S. paratyphi 'AH' and 'BR' antigens were determined following TAB vaccination in control and lindane-fed animals. The titres attained in non-treated controls were higher significantly than those in treated animals indicating a suppressive effect of lindane on humoral immune responses.


Rapid On-Site Detection of the Bursaphelenchus xylophilus Using Recombinase Polymerase Amplification Combined With Lateral Flow Dipstick That Eliminates Interference From Primer-Dependent Artifacts.
The pine wood nematode (PWN), Bursaphelenchus xylophilus, is one of the most lethal nematode species, which causes pine wilt disease (PWD), a devastating forest disease. To date, no effective methods have been developed to control the disease; hence, rapid precise detection of B. xylophilus is of great significance. Traditional molecular diagnostic methods are time-consuming and require sophisticated instruments or skilled operators, which are unavailable in resource-limited settings. A specific, sensitive, and field-applicable diagnostic method is urgently needed. In this study, we developed a diagnostic method using recombinase polymerase amplification combined with lateral flow dipstick (RPA-LFD) for the rapid on-site detection of B. xylophilus. The false-positive signals from primer-dependent artifacts were eliminated using a probe, and base substitutions were included in the primer and probe. The entire detection process for the RPA-LFD assay can be completed under 38°C within approximately 30 min, including 15 min for crude nematode genomic DNA (gDNA) extraction and master mix preparation, 15 min for the RPA-LFD assay. This assay displayed high specificity toward B. xylophilus and showed no cross-reactions with closely related species, including Bursaphelenchus mucronatus and Bursaphelenchus doui. The sensitivity of this assay had a detection limit as low as 1 pg of B. xylophilus purified genomic DNA. Furthermore, the application of the RPA-LFD assay in simulated spiked pinewood samples showed accurate detection results. The RPA-LFD assay in this study successfully detected B. xylophilus in less than 30 min, providing a novel alternative for the simple, sensitive, and specific detection of B. xylophilus and showed potential for B. xylophilus point-of-care testing (POCT) in resource-limited areas or in field.


Drug level monitoring in palliative patients.
Palliative medicine is always patient centred and promotes the principle that no unnecessary investigations are performed. The case is reported of a patient with suspected carbamazepine toxicity presenting as progression of symptoms of primary brain tumour. A comparison is made of the symptoms and signs of toxicity versus tumour, and an aid for deciding when to perform therapeutic drug level monitoring for some common drugs.


Media Use by Children, and Parents' Views on Children's Media Usage.
New (mobile phones, smartphones, tablets, and social media) and traditional media (television) have come to dominate the lives of many children and adolescents. Despite all of this media time and new technology, many parents seem to have few rules regarding the use of media by their children and adolescents. The aim of this study was to evaluate media access/use of children and to evaluate beliefs and attitudes of parents concerning the use of old and new media in Turkey. This is a cross-sectional electronic survey of a national convenience sample in Turkey via SurveyMonkey, including 41 questions regarding topics relevant to television, computers, mobile phones, iPad/tablet use, and social media accounts. The responses of the 333 participants (238 women, 95 men; 27-63 years) were evaluated. The average daily watching alone time was 0 to 2 hours among 53.4% (46/86), and daily coviewing time with parents of children was 0 to 2 hours among 62.7% (54/86) of children below 2 years of age. Regarding parents' monitoring their children's computer use (n=178), 35.4% (63/178) of the parents prefer coviewing, 13.5% of the parents use a family filter (24/178), and 33.1% (59/178) of the parents prefer to check Web history. Approximately 71.2% (237/333) of the participants had an iPad/tablet in the house, 84.3% (200/333) of the parents give their children permission to use the iPad/tablet. Of the parents, 22.5% (45/200) noted that their children used the iPad/tablet at the table during lunch/dinner and 57.9% (26/45) of these children were aged 5 years and below. Of parents, 27.3% (91/333) agreed that the optimal age for owning a mobile phone was 12 years, and 18.0% (60/333) of the parents noted that their children (one-third was below 2 years) used the mobile phone at the table during meals. A total of 33.3% (111/333) children/adolescents have a Facebook profile, and 54.0% (60/111) were below 13 years of age. Approximately 89.2% (297/333) of the parents emphasized that the Internet is essential for their child's education. According to our study results, knowledge regarding the use of old and new media is limited among the parents in Turkey. Our study showed that screen time and mobile device use (including during meals) are common in children below 2 years of age, whereas no screen time was recommended for children below 2 years of age. We concluded that there is need for evidence-based guidelines regarding the use of the Internet and social media for parents and parents should ensure that there is a plan in place for the use of children's media.


A survey assessing the impact of a hospital-based general practice residency program on dentists and dental practice.
The purpose of this survey was to evaluate the outcome of completing a general practice hospital-based dental residency program. A survey was mailed to all individuals who had completed a general practice residency program (resident) between 1980 and 1996 and to dentists who had not completed a hospital program (undergraduate). The responses were evaluated by Fisher's exact test. Seventy-four percent of the resident group and 68% from the undergraduate sample group returned the questionnaire. Approximately half the residents were in general dental practice. Twenty-six percent were involved in specialty dentistry, 7% in hospital dentistry, and 20% in teaching at a dental school. Of the undergraduate dentists, more than three-quarters were in general practice, 5% were entered into specialty programs, 1% were involved in hospital dentistry, and 15% taught at a dental school. Half of the residents held staff privileges in a hospital or ambulatory setting, compared with 16% of undergraduates. Forty-three percent of the residents provided consultation in a hospital or long-term-care facility, compared with 21% of the undergraduates. Practice characteristics suggested enhanced clinical skills in oral surgery, periodontics, emergency dental care, and oral medicine/pathology in those completing the hospital program. The findings of this study confirm that the outcome of completing a hospital program is a change in practice profile, site of practice, services for complex patients, and continuing involvement in teaching.


Is Peer assisted learning better? A modern question to answer: A comparative study.
To determine the effectiveness of peer-assisted learning against expert-assisted learning in terms of scores achieved by medical students, and to assess the perceptions of students about peer-assisted learning. The mixed-method study was conducted at Wah Medical College, Wah Cantonment, Pakistan, from October 2017 to December 2018, and comprised fourth year medical students who were randomised into groups A and B. In the first session the topic 'Data' was taught to group A by a peer and to group B by an expert teacher. In the next session the topic 'Sampling' was taught to group A by an expert teacher and to group B by a peer. Each session was followed by an assessment. Students' views about peer-assisted learning were collected using a predesigned questionnaire. An open-ended question about the role of expert in teaching was also asked from the students. Data was analysed using SPSS 22. Qualitative data was analysed to identify emerging themes. Of the 80 subjects, 41(51.25%) were group A and 39(48.75%) were in group B. Overall, there were 36(45%) males and 44(55%) females. In the first session, mean group A score was 6.85±1.99 and for group B it was 7.54±1.76 (p>0.05). In the second session, the mean score of group A was 6.12±2.06 and for group B it was 4.82±2.01 (p=0.005). Peer-assisted learning was found to be a valuable tool that can be incorporated in the curriculum delivery for easy topics. However the significance of expert's assistance, guidance and feedback cannot be negated.


Identification of diverse microbial metabolites as potent inhibitors of HIV-1 Tat transactivation.
HIV-1 Tat is one of six regulatory proteins that are required for viral replication and is an attractive target for the development of new anti-HIV agents. Screening of microbial extracts using a whole cell Tat-dependent transactivation assay, which guided the separation of the active broths, led to the identification of five structurally diverse classes (M(R) range 232-1126) of natural products. These include i) three sesquiterpenoids, namely, sporogen-AO1, petasol, and 6-dehydropetasol, ii) two resorcylic 14-membered lactones, namely monorden and monocillin IV, iii) a ten-membered lactone, iv) a quinoline and quinoxiline bicyclic octadepsipeptides, namely echinomycin and UK-63598, and v) a cyclic heptapeptide, ternatin. These compounds displayed varying degrees of potencies with IC50 values ranging from 0.0002 to 100 microM. The most active compound was the quinoxiline bicyclic octadepsipeptides, UK-63598, which inhibited Tat-dependent transactivation with an IC50 value of 0.2 nM and exhibited a 100-fold therapeutic window with respect to toxicity. In a single-cycle antiviral assay, UK-6358 inhibited viral replication with an IC50 value of 0.5 nM; however, it appeared to be equally toxic at that concentration. Monocillin IV was significantly less active (Tat transactivation inhibitory IC50 of 5 microM) but was not toxic at 100 microM in an equivalent cytotoxicity assay. The compound exhibited antiviral activity with an IC50 value of 6.2 microM in the single-cycle antiviral assay and a sixfold therapeutic window. Details of the isolation, fermentation, and biological activities of these structurally diverse natural products are described.


Prior probabilities modulate cortical surprise responses: A study of event-related potentials.
The human brain predicts events in its environment based on expectations, and unexpected events are surprising. When probabilistic contingencies in the environment are precisely instructed, the individual can form expectations based on quantitative probabilistic information ('inference-based learning'). In contrast, when probabilistic contingencies are imprecisely instructed, expectations are formed based on the individual's cumulative experience ('experience-based learning'). Here, we used the urn-ball paradigm to investigate how variations in prior probabilities and in the precision of information about these priors modulate choice behavior and event-related potential (ERP) correlates of surprise. In the urn-ball paradigm, participants are repeatedly forced to infer hidden states responsible for generating observable events, given small samples of factual observations. We manipulated prior probabilities of the states, and we rendered the priors calculable or incalculable, respectively. The analysis of choice behavior revealed that the tendency to consider prior probabilities when making decisions about hidden states was stronger when prior probabilities were calculable, at least in some of our participants. Surprise-related P3b amplitudes were observed in both the calculable and the incalculable prior probability condition. In contrast, calculability of prior probabilities modulated anteriorly distributed ERP amplitudes: when prior probabilities were calculable, surprising events elicited enhanced P3a amplitudes. However, when prior probabilities were incalculable, surprise was associated with enhanced N2 amplitudes. Furthermore, interindividual variability in reliance on prior probabilities was associated with attenuated P3b surprise responses under calculable in comparison to incalculable prior probabilities. Our results suggest two distinct neural systems for probabilistic learning that are recruited depending on contextual cues such as the precision of probabilistic information. Individuals with stronger tendencies to rely on calculable prior probabilities seem to have better adapted expectations at their disposal, as indicated by an attenuation of their P3b surprise responses when prior probabilities are calculable.


Alterations in serum anti-alpha-galactosyl antibodies in patients with Crohn's disease and ulcerative colitis.
Anti-galactosyl alpha1-3-galactosyl (anti-Gal) is a natural serum antibody abundantly produced in humans in response to immune stimulation by enteric bacteria. Marked elevation of its titer has been detected in parasitic diseases and in some autoimmune disorders. Because persistent intestinal infection and defective mucosal barrier have been suggested as potential etiologic agents of inflammatory bowel disease, the aim of this study was to analyze the sera levels of anti-Gal antibodies in patients with Crohn's disease and ulcerative colitis. An ELISA assay was performed to analyze circulating antibody using the disaccharide Gal (alpha 1-3)Gal coupled to human serum albumin as antigen and alkaline phosphatase-conjugated rabbit anti-human immunoglobulin G, A, M as antibody. Immunoglobulin classes were assayed using class-specific antibodies. The optical densities of sera from Crohn's disease (1.83 +/- 0.63) and ulcerative colitis (1.45 +/- 0.7) were significantly higher (P < 0.0001 and P < 0.0005, respectively) than those of the control group (0.97 +/- 0.39). In Crohn's disease the increase was distributed among the three immunoglobulin classes; in ulcerative colitis a significant increase was observed only for immunoglobulin A. The increased levels of circulating antibodies against Gal (alpha 1-3)Gal in the presence of intestinal bacterial strains expressing antigenic epitopes and breakdown of mucosal barrier could contribute to the dysregulated immune response observed in inflammatory bowel disease.


Variable-Temperature NMR Spectroscopy, Conformational Analysis, and Thermodynamic Parameters of Cyclic Adenosine 5'-Diphosphate Ribose Agonists and Antagonists.
Cyclic adenosine 5'-diphosphate ribose (cADPR) is a ubiquitous Ca2+-releasing second messenger. Knowledge of its conformational landscape is an essential tool for unraveling the structure-activity relationship (SAR) in cADPR. Variable-temperature 1H NMR spectroscopy, in conjunction with PSEUROT and population analyses, allowed us to determine the conformations and thermodynamic parameters of the furanose rings, γ-bonds (C4'-C5'), and β-bonds (C5'-O5') in the cADPR analogues 2'-deoxy-cADPR, 7-deaza-cADPR, and 8-bromo-cADPR. A significant finding was that, although the analogues are similar to each other and to cADPR itself in terms of overall conformation and population (ΔG°), there were subtle yet important differences in some of thermodynamic properties (ΔH°, ΔS°) associated with each of the conformational equilibria. These differences prompted us to propose a model for cADPR in which the interactions between the A2'-N3, A5″-N3, and H2-R5' atoms serve to fine-tune the N-glycosidic torsion angles (χ).


Genotypic and virulence characteristics of Listeria monocytogenes recovered from food items in Lebanon.
Listeria monocytogenes is the agent of listeriosis, a life threatening foodborne disease for immunocompromised patients and pregnant women. This bacterium is not routinely screened for in Lebanon and there is lack of data about the prevalent strains and their potential pathogenicity. To that purpose, this study was undertaken to characterize L. monocytogenes from various food products, by assessing the in vitro biofilm forming ability, detecting their virulence potential, and characterizing them at the strain level. Fifty-nine isolates were obtained from the Lebanese Agriculture Research Institute (LARI). They were collected in 2012-2013 from local and imported food products in the Lebanese market. Biofilm formation was measured using the Microtiter Plate Assay. PCR amplification was performed for three main virulence genes; hly, actA, and inlB. Pulsed field gel electrophoresis (PFGE) and BIONUMERICS analysis were carried out. Lebanese isolates from cheese and raw meat showed higher biofilm formation than imported and Lebanese seafood isolates. A total of 100% of the isolates were PCR positive for hly and actA genes and 98.3% for inlB gene. PFGE analysis demonstrated the prevalence of 13 different subtypes with 100% similarity. Detected subtypes were grouped into 6 clusters of 90% genomic similarity. Clustered subtypes were particular to the country of origin. This study highlights the presence of L. monocytogenes in the Lebanese food market with high pathogenic potential and stresses the importance of enhanced surveillance and the implementation of strict regulations on local and imported food. Future investigations may be conducted on a larger food selection.


Ultrafast Screening and Quantitation of Pesticides in Food and Environmental Matrices by Solid-Phase Microextraction-Transmission Mode (SPME-TM) and Direct Analysis in Real Time (DART).
The direct interface of microextraction technologies to mass spectrometry (MS) has unquestionably revolutionized the speed and efficacy at which complex matrices are analyzed. Solid Phase Micro Extraction-Transmission Mode (SPME-TM) is a technology conceived as an effective synergy between sample preparation and ambient ionization. Succinctly, the device consists of a mesh coated with polymeric particles that extracts analytes of interest present in a given sample matrix. This coated mesh acts as a transmission-mode substrate for Direct Analysis in Real Time (DART), allowing for rapid and efficient thermal desorption/ionization of analytes previously concentrated on the coating, and dramatically lowering the limits of detection attained by sole DART analysis. In this study, we present SPME-TM as a novel tool for the ultrafast enrichment of pesticides present in food and environmental matrices and their quantitative determination by MS via DART ionization. Limits of quantitation in the subnanogram per milliliter range can be attained, while total analysis time does not exceed 2 min per sample. In addition to target information obtained via tandem MS, retrospective studies of the same sample via high-resolution mass spectrometry (HRMS) were accomplished by thermally desorbing a different segment of the microextraction device.


Shoulder muscle firing patterns during the windmill softball pitch.
The purpose of this study was to describe the activity of eight shoulder muscles during the windmill fast-pitch softball throw. Ten collegiate female pitchers were analyzed with intramuscular electromyography, high-speed cinematography, and motion analysis. The supraspinatus muscle fired maximally during arm elevation from the 6 to 3 o'clock position phase, centralizing the humeral head within the glenoid. The posterior deltoid and teres minor muscles acted maximally from the 3 to 12 o'clock position phase to continue arm elevation and externally rotate the humerus. The pectoralis major muscle accelerated the arm from the 12 o'clock position to ball release phase. The serratus anterior muscle characteristically acted to position the scapula for optimal glenohumeral congruency, and the subscapularis muscle functioned as an internal rotator and to protect the anterior capsule. Although the windmill softball pitch is overtly different from the baseball pitch, several surprising similarities were revealed. The serratus anterior and pectoralis major muscles work in synchrony and seem to have similar functions in both pitches. Although the infraspinatus and teres minor muscles are both posterior cuff muscles, they are characteristically uncoupled during the 6 to 3 o'clock position phase, with the infraspinatus muscle acting more independently below 90 degrees. Subscapularis muscle activity seems important in dynamic anterior glenohumeral stabilization and as an internal rotator in both the baseball and softball throws.


Suppression of corticospinal excitability during negative motor imagery.
To investigate the effect of negative motor imagery on corticospinal excitability, we performed transcranial magnetic stimulation (TMS) studies in seven healthy subjects during imagination of suppressing movements. Subjects were asked to imagine suppression of TMS-induced twitching movement of their nondominant left hands by attempting to increase the amount of relaxation after receiving an auditory NoGo cue (negative motor imagery), but to imagine squeezing hands after a Go cue (positive motor imagery). Single- and paired-pulse TMS were triggered at 2 s after Go or NoGo cues. Motor-evoked potentials (MEPs) were recorded in the first dorsal interosseus (FDI), abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles of the left hand. Paired-pulse TMS with subthreshold conditioning stimuli at interstimulus intervals of 2 (short intracortical inhibition) and 15 ms (intracortical facilitation) and that with suprathreshold conditioning stimuli at interstimulus interval of 80 ms (long intracortical inhibition) were performed in both negative motor imagery and control conditions. Compared with the control state (no imagination), MEP amplitudes of FDI (but not APB and ADM) were significantly suppressed in negative motor imagery, but those from all three muscles were unchanged during positive motor imagery. F-wave responses (amplitudes and persistence) were unchanged during both negative and positive motor imagery. During negative motor imagery, resting motor threshold was significantly increased, but short and long intracortical inhibition and intracortical facilitation were unchanged. The present results demonstrate that excitatory corticospinal drive is suppressed during imagination of suppressing movements.


Plasma Betatrophin Levels of Subjects Classified with Normal, Impaired, and Diabetic Glucose Tolerance, and Subjects with Impaired Fasting Glucose.
This study was aimed to investigate whether betatrophin shows glucose intolerance or not. To access the plasma betatrophin levels after basal and glucose load, groups were classified as normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetic glucose tolerance (DGT) according to WHO 2012 criteria. An oral glucose tolerance test was performed on age-matched subjects (n=220) with a body mass index (BMI)<27 kg/m2. Subjects were categorized as normoglycemic (n=55), IFG (n=50), IGT (n=60), and DM (n=55) according to the WHO criteria. Baseline betatrophin levels in DGT are significantly higher than in NGT (p<0.005), IFG (p<0.004), and IGT (p<0.001). Male subjects have significantly higher betatrophin levels than female subjects (p<0.01). In DGT, betatrophin of male subjects was found to be significantly higher than the betatrophin of male subjects in NGT (p<0.04), IFG (p<0.01), and IGT (p<0.01). Significant relationship between betatrophin and both ages and HbA1c in all groups were observed. When ages were accepted as an independent factor, significant correlation between betatrophin and ages were found. Betatrophin is increased and associated with age and HbA1c in DGT. Males had higher betatrophin levels compared with females in DGT group. As no obvious betatrophin deficiency to substitute in IFG and IGT individuals were observed, betatrophin levels appeared to be related to the pathogenesis of the diabetic stages rather than prediabetic stages.


Reinstatement of conditioned fear and the hippocampus: an attentional-associative model.
An existing attentional-associative model of classical conditioning [Schmajuk N, Lam Y, Gray JA. Latent inhibition: a neural network approach. J Exp Psychol: Anim Behav Process 1996;22:321-49] is applied to the description of reinstatement in animals and humans. According to the model, inhibitory associations between the context (CX) and unconditioned stimulus (US) are formed during extinction, which help preserve the association between the conditioned stimulus (CS) and the US. However, summation and retardation tests fail to reveal these associations because (a) the CX is not attended or (b) a CX-CS configural stimulus formed during extinction is both poorly attended and weakly active during testing. When US presentations and testing occur in the same context, reinstatement is the consequence of a decreased CX inhibition and the increased attention to the CS, which activates the remaining CS-US association. When US presentations occur in the context of extinction but the CS is tested in a different context, reinstatement results from an increased attention to the CS and the combination of CS-CX and CX-US excitatory associations. The assumption that associations between CSs are impaired following neurotoxic hippocampal lesions or in amnesia, is sufficient to describe absence of reinstatement in those cases. However, additional assumptions might be needed to describe the effect of hippocampal lesions on other postextinction manipulations.


Complete Genome Sequence of Campylobacter concisus ATCC 33237T and Draft Genome Sequences for an Additional Eight Well-Characterized C. concisus Strains.
We report the complete genome sequence of the Campylobacter concisus type strain ATCC 33237 and the draft genome sequences of eight additional well-characterized C. concisus strains. C. concisus has been shown to be a genetically heterogeneous species, and these nine genomes provide valuable information regarding the diversity within this taxon.


Engineered Multivalency Enhances Affibody-Based HER3 Inhibition and Downregulation in Cancer Cells.
The receptor tyrosine kinase HER3 has emerged as a therapeutic target in ovarian, prostate, breast, lung, and other cancers due to its ability to potently activate the PI3K/Akt pathway, especially via dimerization with HER2, as well as for its role in mediating drug resistance. Enhanced efficacy of HER3-targeted therapeutics would therefore benefit a wide range of patients. This study evaluated the potential of multivalent presentation, through protein engineering, to enhance the effectiveness of HER3-targeted affibodies as alternatives to monoclonal antibody therapeutics. Assessment of multivalent affibodies on a variety of cancer cell lines revealed their broad ability to improve inhibition of Neuregulin (NRG)-induced HER3 and Akt phosphorylation compared to monovalent analogues. Engineered multivalency also promoted enhanced cancer cell growth inhibition by affibodies as single agents and as part of combination therapy approaches. Mechanistic investigations revealed that engineered multivalency enhanced affibody-mediated HER3 downregulation in multiple cancer cell types. Overall, these results highlight the promise of engineered multivalency as a general strategy for enhanced efficacy of HER3-targeted therapeutics against a variety of cancers.


Characterization of Portuguese honey from Castelo Branco region according to their pollen spectrum, physicochemical characteristics and mineral contents.
The aim of this work was to evaluate the quality of 16 honey samples from Castelo Branco region (Portugal). Twelve are monofloral from Calluna vulgaris, Erica, Lavandula, Echium and Campanula. The mean values obtained for physicochemical parameters were: 3.82 pH; 16.80% moisture; 81.6°Brix; 0.21% ash; 357.6 μS cm-1 electrical conductivity; 33.7 meq/kg free acidity; 5.7 meq/kg lactonic acidity; 39.3 meq/kg total acidity; 9.11 mg/kg HMF; 21.3 IN invertase and 9.0° Gothe for diastase activities. The results indicate a good quality, adequate processing, good maturity and freshness of honey. Additionally, the determination of mineral contents revealed that the K was the major element. Mean values obtained were (mg/kg): Ca, 28.36; K, 701.87; Mg, 74.00; Na, 31.04; Fe, 097; Cu, 0.65; Zn, 1.23; Mn, 2.78 and P, 48.80. Among the overall determined parameters, CB2 stands out by its high values in minerals, pH, moisture, ash, electrical conductivity and enzyme activity.


Machine vision-based Statistical texture analysis techniques for characterization of liver tissues using CT images.
To characterize human liver tissues by demonstrating the ability of machine vision, and to propose a new auto-generated report based on texture analysis that may work with co-occurrence matrix statistics. The retrospective study was conducted at Bahawal Victoria Hospital (BVH), Bahawalpur, Pakistan, and comprised clinically verified computed tomography imaging data between October 2018 and September 2020. The image samples and related data were used to segregate classes 1-4. Appropriate image classes belonging to the same disease were trained to confirm the abnormalities in liver tissues using supervised learning methods, principal component analysis, linear discriminant analysis, and non-linear discriminant analysis. Robust and reliable texture features were investigated by generating testing classes. Overall performance of the presented machine vision approach was analyzed using four parameters; precision, recall/sensitivity, F1-score, and accuracy. Statistical analysis was done using B11 software. There were 312 image samples from 71 patients; 51(71.8%) males and 20(28.2%) females. Among the patients, 19(26.7%) had abscess, 15(21.1%) had metastatic disease, 23(32.4%) had tumour necrosis, 6(8.5%) had vascular disorder, and 8(11.3%) were normal. Principal component analysis, linear discriminant analysis, and non-linear discriminant analysis showed high >97.86% values, but the discrimination rate was 100% for class 4. Abnormalities in the human liver could be discriminated and diagnosed by texture analysis techniques using second-order statistics that may assist the radiologist and medical physicists in predicting the severity and proliferation of abnormalities in liver diseases.


Exploration of the Key Factors for Optimizing the in Vivo Oral Delivery of Insulin by Using a Noncovalent Strategy with Cell-Penetrating Peptides.
This present study aimed to determine the optimal oral insulin delivery conditions that would maximize the utility of cell-penetrating peptides (CPPs) by using a noncovalent strategy. We first compared the effectiveness of two potential CPPs, penetratin and its analog PenetraMax, as absorption enhancers for insulin. The combined effect was evaluated under in vivo oral administration conditions. Both D-forms of CPPs were highly effective for increasing the oral absorption of insulin, and D-PenetraMax showed a more rapid onset of absorption enhancement effects compared with those of D-penetratin. However, synergistic absorption enhancement effects after combination treatment were not observed. Next, we tried a theoretical approach to establish optimized oral insulin delivery conditions. A surface plasmon resonance (SPR)-based analysis demonstrated that binding between insulin and penetratin (2 mM) might be saturated at 100-500 µM penetratin, while the bound concentration of penetratin could increase in accordance with an increased concentration of mixed insulin. To test this hypothesis, we investigated the effectiveness of different insulin doses in the gastric pH-neutralized mice. The results showed that the dissociation of noncovalent complexes of insulin and CPPs at the low gastric pH was prevented in these mice. Our findings clearly suggested that a noncovalent strategy with CPPs represents an effective approach for the L-form of CPP to increase the concentration of CPP-bound insulin to attain greater absorption of insulin, although this approach may not be appropriate for the D-form of CPP. Our findings will contribute to the development of oral dosage forms of insulin for noncovalent strategies involving CPP.


Prediction of porosity of food materials during drying: Current challenges and directions.
Pore formation in food samples is a common physical phenomenon observed during dehydration processes. The pore evolution during drying significantly affects the physical properties and quality of dried foods. Therefore, it should be taken into consideration when predicting transport processes in the drying sample. Characteristics of pore formation depend on the drying process parameters, product properties and processing time. Understanding the physics of pore formation and evolution during drying will assist in accurately predicting the drying kinetics and quality of food materials. Researchers have been trying to develop mathematical models to describe the pore formation and evolution during drying. In this study, existing porosity models are critically analysed and limitations are identified. Better insight into the factors affecting porosity is provided, and suggestions are proposed to overcome the limitations. These include considerations of process parameters such as glass transition temperature, sample temperature, and variable material properties in the porosity models. Several researchers have proposed models for porosity prediction of food materials during drying. However, these models are either very simplistic or empirical in nature and failed to consider relevant significant factors that influence porosity. In-depth understanding of characteristics of the pore is required for developing a generic model of porosity. A micro-level analysis of pore formation is presented for better understanding, which will help in developing an accurate and generic porosity model.


Characterization of a Mixture of CO2 Adsorption Products in Hyperbranched Aminosilica Adsorbents by (13)C Solid-State NMR.
Hyperbranched amine polymers (HAS) grown from the mesoporous silica SBA-15 (hereafter "SBA-15-HAS") exhibit large capacities for CO2 adsorption. We have used static in situ and magic-angle spinning (MAS) ex situ (13)C nuclear magnetic resonance (NMR) to examine the adsorption of CO2 by SBA-15-HAS. (13)C NMR distinguishes the signal of gas-phase (13)CO2 from that of the chemisorbed species. HAS polymers possess primary, secondary, and tertiary amines, leading to multiple chemisorption reaction outcomes, including carbamate (RnNCOO(-)), carbamic acid (RnNCOOH), and bicarbonate (HCO3(-)) moieties. Carbamates and bicarbonate fall within a small (13)C chemical shift range (162-166 ppm), and a mixture was observed including carbamic acid and carbamate, the former disappearing upon evacuation of the sample. By examining the (13)C-(14)N dipolar coupling through low-field (B0 = 3 T) (13)C{(1)H} cross-polarization MAS NMR, carbamate is confirmed through splitting of the (13)C resonance. A third species that is either bicarbonate or a second carbamate is evident from bimodal T2 decay times of the ∼163 ppm peak, indicating the presence of two species comprising that single resonance. The mixture of products suggests that (1) the presence of amines and water leads to bicarbonate being present and/or (2) the multiple types of amine sites in HAS permit formation of chemically distinct carbamates.


Maize dry matter production and macronutrient extraction model as a new approach for fertilizer rate estimation.
Decision support for nutrient application remains an enigma if based on soil nutrient analysis. If the crop could be used as an auxiliary indicator, the plant nutrient status during different growth stages could complement the soil test, improving the fertilizer recommendation. Nutrient absorption and partitioning in the plant are here studied and described with mathematical models. The objective of this study considers the temporal variation of the nutrient uptake rate, which should define crop needs as compared to the critical content in soil solution. A uniform maize crop was grown to observe dry matter accumulation and nutrient content in the plant. The dry matter accumulation followed a sigmoidal model and the macronutrient content a power model. The maximum nutrient absorption occurred at the R4 growth stage, for which the sap concentration was successfully calculated. It is hoped that this new approach of evaluating nutrient sap concentration will help to develop more rational ways to estimate crop fertilizer needs. This new approach has great potential for on-the-go crop sensor-based nutrient application methods and its sensitivity to soil tillage and management systems need to be examined in following studies. If mathematical model reflects management impact adequately, resources for experiments can be saved.


Global nursing leadership: a professional imperative.
Globalization is an inevitable trend in the modern world, as our communities become both closer and more diverse. Globalization is examined in this report as a key factor in recognizing the intersection of health and development. Nurse leaders face the crucial need to understand and take initiatives in responding to this radically changing world. The transformation of nursing requires active participation and leadership in practice, education, research, and policy arenas. To participate in shaping the public understanding of health and development, nurse leaders must be included in the multinational and multidisciplinary decision processes that shape health care at home and abroad.


ResNet-SVM: Fusion based glioblastoma tumor segmentation and classification.
Computerized segmentation of brain tumor based on magnetic resonance imaging (MRI) data presents an important challenging act in computer vision. In image segmentation, numerous studies have explored the feasibility and advantages of employing deep neural network methods to automatically detect and segment brain tumors depicting on MRI. For training the deeper neural network, the procedure usually requires extensive computational power and it is also very time-consuming due to the complexity and the gradient diffusion difficulty. In order to address and help solve this challenge, we in this study present an automatic approach for Glioblastoma brain tumor segmentation based on deep Residual Learning Network (ResNet) to get over the gradient problem of deep Convolutional Neural Networks (CNNs). Using the extra layers added to a deep neural network, ResNet algorithm can effectively improve the accuracy and the performance, which is useful in solving complex problems with a much rapid training process. An additional method is then proposed to fully automatically classify different brain tumor categories (necrosis, edema, and enhancing regions). Results confirm that the proposed fusion method (ResNet-SVM) has an increased classification results of accuracy (AC = 89.36%), specificity (SP = 92.52%) and precision (PR = 90.12%) using 260 MRI data for the training and 112 data used for testing and validation of Glioblastoma tumor cases. Compared to the state-of-the art methods, the proposed scheme provides a higher performance by identifying Glioblastoma tumor type.


Bivalent Metal-Chelating Properties of Harzianic Acid Produced by Trichoderma pleuroticola Associated to the Gastropod Melarhaphe neritoides.
Harzianic acid is a secondary metabolite of Trichoderma, structurally belonging to the dienyltetramic acid subgroup of the tetramic acids. Biological activities of harzianic acid are of great interest for its antimicrobial and plant growth-promoting activities, which might be related to its chelating properties. In the present work harzianic acid, isolated from cultures of a strain of Trichoderma pleuroticola associated to the gastropod Melarhaphe neritoides, was studied as a complexant agent of a number of biologically relevant transition metals (i.e., Zn2+, Fe2+, Cu2+, and Mn2+), using UV-VIS, potentiometry, MS and NMR techniques. Our findings show the coordination capacity of harzianic acid toward the above cations through the formation of neutral or charged complexes in a variable ratio depending on the metal and pH conditions.


Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment ("chemobrain").
Chemotherapy-induced cognitive impairment (CICI) is now widely recognized as a real and too common complication of cancer chemotherapy experienced by an ever-growing number of cancer survivors. Previously, we reported that doxorubicin (Dox), a prototypical reactive oxygen species (ROS)-producing anti-cancer drug, results in oxidation of plasma proteins, including apolipoprotein A-I (ApoA-I) leading to tumor necrosis factor-alpha (TNF-α)-mediated oxidative stress in plasma and brain. We also reported that co-administration of the antioxidant drug, 2-mercaptoethane sulfonate sodium (MESNA), prevents Dox-induced protein oxidation and subsequent TNF-α elevation in plasma. In this study, we measured oxidative stress in both brain and plasma of Dox-treated mice both with and without MESNA. MESNA ameliorated Dox-induced oxidative protein damage in plasma, confirming our prior studies, and in a new finding led to decreased oxidative stress in brain. This study also provides further functional and biochemical evidence of the mechanisms of CICI. Using novel object recognition (NOR), we demonstrated the Dox administration resulted in memory deficits, an effect that was rescued by MESNA. Using hydrogen magnetic resonance imaging spectroscopy (H1-MRS) techniques, we demonstrated that Dox administration led to a dramatic decrease in choline-containing compounds assessed by (Cho)/creatine ratios in the hippocampus in mice. To better elucidate a potential mechanism for this MRS observation, we tested the activities of the phospholipase enzymes known to act on phosphatidylcholine (PtdCho), a key component of phospholipid membranes and a source of choline for the neurotransmitter, acetylcholine (ACh). The activities of both phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D were severely diminished following Dox administration. The activity of PC-PLC was preserved when MESNA was co-administered with Dox; however, PLD activity was not protected. This study is the first to demonstrate the protective effects of MESNA on Dox-related protein oxidation, cognitive decline, phosphocholine (PCho) levels, and PC-PLC activity in brain and suggests novel potential therapeutic targets and strategies to mitigate CICI.


Wild-type MIC distributions and epidemiological cutoff values for posaconazole and voriconazole and Candida spp. as determined by 24-hour CLSI broth microdilution.
We tested 16,191 strains of Candida against posaconazole and voriconazole, using the CLSI M27-A3 broth microdilution (BMD) method (24-h incubation), in order to define wild-type (WT) populations and epidemiological cutoff values (ECVs). From 2001 to 2009, 8,619 isolates of Candida albicans, 2,415 isolates of C. glabrata, 2,278 isolates of C. parapsilosis, 1,895 isolates of C. tropicalis, 508 isolates of C. krusei, 205 isolates of C. lusitaniae, 177 isolates of C. guilliermondii, and 93 isolates of C. kefyr were obtained from over 100 centers worldwide. The modal MICs (μg/ml) for posaconazole and voriconazole, respectively, were as follows: for C. albicans, 0.016 and 0.007; for C. glabrata, 0.5 and 0.06; for C. parapsilosis, 0.06 and 0.007; for C. tropicalis, 0.03 and 0.015; for C. krusei, 0.25 and 0.12; for C. lusitaniae, 0.03 and 0.007; for C. guilliermondii, 0.12 and 0.03; and for C. kefyr, 0.06 and 0.007. The ECVs (μg/ml [% of isolates that had MICs equal to or less than the ECV]) for posaconazole and voriconazole, respectively, were as follows: 0.06 (98.5) and 0.03 (98.9) for C. albicans, 2 (96.2) and 0.5 (90.4%) for C. glabrata, 0.25 (99.3) and 0.12 (97.9) for C. parapsilosis, 0.12 (97.6) and 0.06 (97.2) for C. tropicalis, 0.5 (99.8) and 0.5 (99.4) for C. krusei, 0.12 (95.6) and 0.03 (96.6) for C. lusitaniae, 0.5 (98.9) and 0.25 (98.3) for C. guilliermondii, and 0.25 (100.0) and 0.015 (100.0) for C. kefyr. In the absence of clinical breakpoints (CBPs) for posaconazole, these WT distributions and ECVs will be useful in surveillance for emergence of reduced susceptibility to posaconazole among Candida spp. Whereas a CBP for susceptibility of ≤ 1 μg/ml has been established for voriconazole and all species of Candida, it is notable that ECVs for this agent range from 10- to >100-fold lower than the CBP, depending on the species of Candida. The CBP is inadequate in detecting the emergence of voriconazole resistance among most Candida species encountered clinically. The CBPs for voriconazole should be reassessed, with consideration for development of species-specific CBPs.


Re-evaluating diabetic papillopathy using optical coherence tomography and inner retinal sublayer analysis.
To re-evaluate diabetic papillopathy using optical coherence tomography (OCT) for quantitative analysis of the peripapillary retinal nerve fibre layer (pRNFL), macular ganglion cell layer (mGCL) and inner nuclear layer (mINL) thickness. In this retrospective observational case series between June 2008 and July 2019 at Moorfields Eye hospital, 24 eyes of 22 patients with diabetes and optic disc swelling with confirmed diagnosis of NAION or diabetic papillopathy by neuro-ophthalmological assessment were included for evaluation of the pRNFL, mGCL and mINL thicknesses after resolution of optic disc swelling. The mean age of included patients was 56.5 (standard deviation (SD) ± 14.85) years with a mean follow-up duration of 216 days. Thinning of pRNFL (mean: 66.26, SD ± 31.80 µm) and mGCL (mean volume: 0.27 mm3, SD ± 0.09) were observed in either group during follow-up, the mINL volume showed no thinning with 0.39 ± 0.05 mm3. The mean decrease in visual acuity was 4.13 (SD ± 14.27) ETDRS letters with a strong correlation between mGCL thickness and visual acuity (rho 0.74, p < 0.001). After resolution of acute optic disc swelling, atrophy of pRNFL and mGCL became apparent in all cases of diabetic papillopathy and diabetic NAION, with preservation of mINL volumes. Analysis of OCT did not provide a clear diagnostic distinction between both entities. We suggest a diagnostic overlay with the degree of pRNFL and mGCL atrophy of prognostic relevance for poor visual acuity independent of the semantics of terminology.


Confidence in dementia care and care approach toward dementia among the nursing staff in long-term care facilities in China: a cross-sectional survey.
Confidence and appropriate care approach toward dementia among nursing staff (nurses and care assistants) are crucial manifestations of competency to deal with the complexity of dementia care in long-term care facilities (LTCFs). The purpose of this study was to investigate the confidence in dementia care and care approach among nursing staff in LTCFs in mainland China. A cross-sectional study design was utilized in LTCFs in Shandong Province, mainland China. A convenient sample included of 317 nursing staff drawn from 15 LTCFs. Survey questions included (a) demographics, (b) dementia knowledge, (c) dementia care confidence, and (d) approach to care for people with dementia. Data were analyzed with descriptive statistics. Factors associated with confidence and care approach for people with dementia were examined using Pearson's correlation and multivariate regression analyses. Dementia care confidence was generally moderate. Factors affecting confidence to care for people with dementia included educational level, months of caring dementia patients, and dementia knowledge. Most nursing staff did not use a person-centered care approach which was significantly associated with their age, dementia-learning experience, and knowledge and confidence toward caring for people with dementia. A positive correlation was identified between confidence to care for people with dementia and nursing staff care approach. Clinical recommendations are provided to further develop education strategies tailored for nursing staff to meet the growing demand for dementia care services.